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dc.contributor.authorLi, Huapeng
dc.contributor.authorLi, Qi
dc.contributor.authorDang, Kyvan
dc.contributor.authorMa, Shan
dc.contributor.authorCotton, Jennifer L.
dc.contributor.authorYang, Sun
dc.contributor.authorZhu, Lihua Julie
dc.contributor.authorDeng, April C.
dc.contributor.authorIp, Y. Tony
dc.contributor.authorJohnson, Randy L.
dc.contributor.authorWu, Xu
dc.contributor.authorPunzo, Claudio
dc.contributor.authorMao, Junhao
dc.date2022-08-11T08:09:55.000
dc.date.accessioned2022-08-23T16:48:35Z
dc.date.available2022-08-23T16:48:35Z
dc.date.issued2019-12-03
dc.date.submitted2020-01-02
dc.identifier.citation<p>Cell Rep. 2019 Dec 3;29(10):3200-3211.e4. doi: 10.1016/j.celrep.2019.03.021. <a href="https://doi.org/10.1016/j.celrep.2019.03.021">Link to article on publisher's site</a></p>
dc.identifier.issn2211-1247 (Electronic)
dc.identifier.doi10.1016/j.celrep.2019.03.021
dc.identifier.pmid31801083
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41301
dc.description.abstractUveal melanoma (UM), the most common ocular malignancy, is characterized by GNAQ/11 mutations. Hippo/YAP and Ras/mitogen-activated protein kinase (MAPK) emerge as two important signaling pathways downstream of G protein alpha subunits of the Q class (GalphaQ/11)-mediated transformation, although whether and how they contribute to UM genesis in vivo remain unclear. Here, we adapt an adeno-associated virus (AAV)-based ocular injection method to directly deliver Cre recombinase into the mouse uveal tract and demonstrate that Lats1/2 kinases suppress UM formation specifically in uveal melanocytes. We find that genetic activation of YAP, but not Kras, is sufficient to initiate UM. We show that YAP/TAZ activation induced by Lats1/2 deletion cooperates with Kras to promote UM progression via downstream transcriptional reinforcement. Furthermore, dual inhibition of YAP/TAZ and Ras/MAPK synergizes to suppress oncogenic growth of human UM cells. Our data highlight the functional significance of Lats-YAP/TAZ in UM initiation and progression in vivo and suggest combination inhibition of YAP/TAZ and Ras/MAPK as a new therapeutic strategy for UM.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31801083&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright 2019 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectAAV ocular injection
dc.subjectHippo/YAP
dc.subjectRas/MAPK
dc.subjectdual inhibition
dc.subjectmouse model
dc.subjecttumor initiation
dc.subjecttumor progression
dc.subjectuveal melanoma
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectCancer Biology
dc.subjectEnzymes and Coenzymes
dc.subjectEye Diseases
dc.subjectMolecular Biology
dc.subjectNeoplasms
dc.subjectOphthalmology
dc.subjectPathology
dc.titleYAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression
dc.typeJournal Article
dc.source.journaltitleCell reports
dc.source.volume29
dc.source.issue10
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5106&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4087
dc.identifier.contextkey16101189
refterms.dateFOA2022-08-23T16:48:35Z
html.description.abstract<p>Uveal melanoma (UM), the most common ocular malignancy, is characterized by GNAQ/11 mutations. Hippo/YAP and Ras/mitogen-activated protein kinase (MAPK) emerge as two important signaling pathways downstream of G protein alpha subunits of the Q class (GalphaQ/11)-mediated transformation, although whether and how they contribute to UM genesis in vivo remain unclear. Here, we adapt an adeno-associated virus (AAV)-based ocular injection method to directly deliver Cre recombinase into the mouse uveal tract and demonstrate that Lats1/2 kinases suppress UM formation specifically in uveal melanocytes. We find that genetic activation of YAP, but not Kras, is sufficient to initiate UM. We show that YAP/TAZ activation induced by Lats1/2 deletion cooperates with Kras to promote UM progression via downstream transcriptional reinforcement. Furthermore, dual inhibition of YAP/TAZ and Ras/MAPK synergizes to suppress oncogenic growth of human UM cells. Our data highlight the functional significance of Lats-YAP/TAZ in UM initiation and progression in vivo and suggest combination inhibition of YAP/TAZ and Ras/MAPK as a new therapeutic strategy for UM.</p>
dc.identifier.submissionpathoapubs/4087
dc.contributor.departmentDepartment of Pathology
dc.contributor.departmentDepartment of Ophthalmology and Visual Sciences
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentDepartment of Molecular, Cell and Cancer Biology
dc.source.pages3200-3211.e4


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Copyright 2019 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Except where otherwise noted, this item's license is described as Copyright 2019 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).